Inhibition of TRPV4 Regulates Mitophagy Through the Sirt1/FoxO1 Signaling Pathway To Alleviate Acute Lung Injury

The transient receptor potential vanilloid 4 (TRPV4) channel has emerged as a key mediator of calcium dysregulation in acute lung injury (ALI), but its role in mitophagy-the selective autophagic clearance of dysfunctional mitochondria-and crosstalk with the Sirtuin 1(Sirt1)signaling axis remain unclear. Lipopolysaccharide (LPS) induced the upregulation of TRPV4, oxidative stress (ROS), and apoptosis in both in vivo and in vitro models. TRPV4 activation (GSK1016790A) exacerbated ALI by impairing mitophagy, as evidenced by reduced LC3/Translocase of the outer mitochondrial membrane 20 (TOMM20) co-localization and decreased PTEN induced kinase 1(PINK1)/PARK2 expression. Conversely, TRPV4 inhibition (GSK2193874) or knockout attenuated lung injury, enhanced mitophagic flux, and reduced mitochondrial damage. Mechanistically, TRPV4 inhibition upregulated Sirt1/Forkhead box O1(FoxO1) signaling, driving PINK1/PARK2-dependent mitophagy. Sirt1 inhibition abrogated these protective effects, confirming its critical role in the TRPV4-mitophagy axis. TRPV4 knockout༈Trpv4⁻/⁻༉mice exhibited reduced pulmonary inflammation, apoptosis, and improved mitochondrial ultrastructure compared to wild-type controls.TRPV4 exacerbated LPS-induced ALI by suppressing Sirt1/FoxO1-mediated mitophagy. Genetic or pharmacological inhibition of TRPV4 restored mitophagic clearance of dysfunctional mitochondria, offering a promising therapeutic strategy for septic ALI. These findings highlighted the TRPV4-Sirt1/FoxO1 axis as a novel target for improving outcomes in critical care settings.